1. Field of the Invention
This invention relates to sulfonylethyl and thioethyl phosphorodiamidates, formulations containing them, their pharmaceutical use, and their preparation and intermediates in their preparation.
2. Description of the Related Art
U.S. Pat. No. 5,556,942 [and PCT Publication No. WO 95/09865] discloses compounds of the formula
and their amides, esters, and salts, where:L is an electron withdrawing leaving group;Sx is —S(═O)—, —S(═O)2—, —S(═NH)—, —S(═O)(═NH)—, —S+(C1-C6 alkyl)-, —Se(═O)—, —Se(═O)2—, —Se(═NH)—, or —Se(═O)(═NH)—, or is —O—C(═O)—, or —HN—C(═O)—;each R1, R2 and R3 is independently H or a non-interfering substituent;n is 0, 1 or 2;Y is selected from the group consisting of
where m is 1 or 2; andAAc is an amino acid linked through a peptide bond to the remainder of the compound.
The compounds are stated to be useful drugs for the selective treatment of target tissues which contain compatible GST isoenzymes, and simultaneously elevate the levels of GM progenitor cells in bone marrow. Disclosed embodiments for L include those that generate a drug that is cytotoxic to unwanted cells, including the phosphoramidate and phosphorodiamidate mustards.
One of the compounds has the formula
It is referred to in the patent as TER 286 and named as γ-glutamyl-α-amino-β-((2-ethyl-N,N,N,N-tetra(2′-chloro)ethylphosphoramidate)sulfonyl)propionyl-(R)-(−)-phenylglycine. This compound, later referred to as TLK286, has the CAS name L-γ-glutamyl-3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfonyl]-L-alanyl-2-phenyl-(2R)-glycine. As the neutral compound, its proposed International Nonproprietary Name is canfosfamide; and as its hydrochloride acid addition salt, its United States Adopted Name is canfosfamide hydrochloride. Canfosfamide and its salts are anticancer compounds that are activated by the actions of GST P1-1, and by GST A1-1, to release the cytotoxic phosphorodiamidate mustard moiety.
In vitro, canfosfamide has been shown to be more potent in the M6709 human colon carcinoma cell line selected for resistance to doxorubicin and the MCF-7 human breast carcinoma cell line selected for resistance to cyclophosphamide, both of which overexpress GST P1-1, over their parental cell lines; and in murine xenografts of M7609 engineered to have high, medium, and low levels of GST P1-1, the potency of canfosfamide hydrochloride was positively correlated with the level of GST P1-1 (Morgan et al., Cancer Res., 58:2568 (1998)).
Canfosfamide hydrochloride is currently being evaluated in multiple clinical trials for the treatment of ovarian, breast, non-small cell lung, and colorectal cancers. It has demonstrated significant single agent antitumor activity and improvement in survival in patients with non-small cell lung cancer and ovarian cancer, and single agent antitumor activity in colorectal and breast cancer. Evidence from in vitro cell culture and tumor biopsies indicates that canfosfamide is non-cross-resistant to platinum, paclitaxel, and doxorubicin (Rosario et al., Mol. Pharmacol., 58:167 (2000)), and also to gemcitabine. Patients treated with canfosfamide hydrochloride show a very low incidence of clinically significant hematological toxicity.
PCT Publication No. WO 95/09865 also discloses intermediates that are compounds of the formula
and their amides, esters, and salts, where:L is an electron withdrawing leaving group;S+ is S or Se;S* is —S(═O)—, —S(═O)2—, —S(═NH)—, —S(═O)(═NH)—, —S+(C1-C6 alkyl)-, —Se(═O)—, —Se(═O)2—, —Se(═NH)—, or —Se(═O)(═NH)—, or is —O—C(═O)—, or —HN—C(═O)—;each R1, R2 and R3 is independently H or a non-interfering substituent;n is 0, 1 or 2;Y is selected from the group consisting of
where m is 1 or 2; andAAc is an amino acid linked through a peptide bond to the remainder of the compound.
U.S. Pat. No. 6,506,739 [and PCT Publication No. WO 01/83496] discloses compounds of the formula
where:X is a halogen atom;Q is O, S, or NH; andR is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or is R′CO—, R′NHCO—, R′SO2—, or R′NHSO2— where R′ is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R—Q together is chlorine; and their salts.
The compounds are stated to be antitumor agents.
It would be desirable to develop other anticancer drugs having an efficacy and safety as good or better than canfosfamide and other compounds of U.S. Pat. No. 5,556,942.
The disclosures of U.S. Pat. Nos. 5,556,942 and 6,506,739, and the disclosures of other documents referred to in this application, are incorporated into this application by reference.